For the past 2 years, staff at the small herb company Herbs, Etc. has been preparing for an inspection of Good Manufacturing Practices (GMP) from the US Food and Drug Administration (FDA). In hopes of being GMP-compliant, many of the 27 employees have attended GMP seminars and webinars, thoroughly read and reread FDA’s GMP rule, and discussed the rule section-bysection in weekly meetings. Additionally, they have upgraded certain aspects of the company’s operations, including the hiring of a new full-time employee to review and approve manufacturing documentation for quality assurance purposes. Though it has been a tremendous amount of work, Daniel Gagnon, owner of the Santa Fe, New Mexico-based Herbs, Etc., said he is glad the GMP rule has been implemented.
“These regulations were really needed,” said Gagnon (oral communication, August 31, 2009).
FDA issued the final rule on GMPs for dietary supplements on June 25, 2007.1 According to the rule, compliance with GMPs (sometimes referred to as cGMPs) should help to ensure that manufacturers are producing unadulterated and properly-labeled dietary supplements and using a consistent and reliable process. The final rule applies to all domestic and foreign companies that manufacture, package, label, or hold dietary supplements distributed in the United States. The compliance requirements are being implemented in 3 phases: large companies (more than 500 employees) needed to be compliant by June 25, 2008; small companies (fewer than 500 but more than 20 employees) needed to be compliant by June 25, 2009; and very small companies (less than 20 employees) have until June 25, 2010, to be compliant.
The generalized activities necessary for GMP compliance include:
- Having qualified staff members employed
- Having physical plants designed or built to protect against adulteration
- The use of appropriate equipment and utensils
- The use of master manufacturing and batch production records
- Employing quality control procedures
- Holding and distributing dietary supplements and manufacturing materials in ways that ensure that quality is not negatively affected
- Recording each product’s GMP-related complaints and retaining these records for 1 to 2 years
Industry reaction to the final rule has included criticism of FDA’s lack of specific guidance for manufacturers and concerns regarding potential costs for small and very small businesses.1,2 Feedback has especially focused on the wording, organization, and length of the rule, which many consider confusing. FDA is currently being sued by a group of plaintiffs who claim the agency is violating the Fifth Amendment requirement that laws not be vague, alleging that some supplement manufacturers are unable to understand the rule.3 Though this lawsuit lacks probability of success, it voices concerns held by some in the industry.
The American Herbal Products Association (AHPA), the leading trade association focused exclusively on botanicals, petitioned FDA in July of 2007 to reconsider and amend 7 aspects of the final rule for being potentially confusing, destructive to dietary ingredient manufacturers, or contrary to the public interest.4
“They ignored us,” said Michael McGuffin, president of AHPA (oral communication, August 26, 2009).
Other trade associations have voiced similar concerns. The Council for Responsible Nutrition (CRN), a trade group representing many large dietary ingredient and dietary supplement companies, commented in October of 2007 that it strongly opposes the rule’s inclusion of the Petition to Request an Exemption From 100 Percent Identity Testing of Dietary Ingredients.5 The Natural Products Association (NPA), the trade association for health food retailers and manufacturers, meanwhile, requested that FDA provide a definition or guidance on how to properly qualify suppliers of dietary ingredients.6 FDA is working on releasing such guidance, but nothing has been published thus far.
FDA Inspection Activities
FDA says it is limiting “any disruption for dietary supplements produced by small businesses” by enforcing compliance requirements in phases based on business size, but it also recognizes that the rule will have a “significant economic effect on small businesses.”1 The agency estimated that the annual costs of GMP compliance would be $69,000 per year for large businesses and $46,000 for very small businesses, with small businesses bearing the largest costs at $184,000. Though many have commented that FDA’s figures are largely underestimated, Brad Williams, a manager in FDA’s Division of Dietary Supplements, said it is too soon to analyze the actual costs for companies (oral communication, August 27, 2009).
As of August 9, 2009, FDA had inspected 12 large manufacturers, said Williams. He added that the agency encountered difficulty in correctly identifying manufacturer size during the first phase of inspections. Initially relying upon company sales as an indicator of company size, it soon became apparent that many smaller companies have significant sales. If inspectors happened to show up to what they believed was a large manufacturer, and discovered it wasn’t, the company was inspected according to food GMPs, said Williams. (Prior to the implementation of the dietary supplement GMPs, all dietary supplement manufacturers had to comply with existing GMPs for food manufacturers, which are oriented towards ensuring proper sanitation measures.)
Of the 12 manufacturers inspected, FDA issued only one untitled letter, which is less severe than a warning letter, to a New Jersey firm, and the manufacturer is currently making corrections, said Williams. This doesn’t mean all other companies were without errors, however.
“We have not found perfect compliance everywhere,” he added.
FDA expects to begin inspecting small businesses very soon, and inspections of large firms will continue. After June 2010, all firms must comply, irrespective of their size. Although a 2008 FDA report estimated that more than 200 companies would be inspected during the 2009 fiscal year, it is now known that the number will be much less.
“Actually, we won’t come close to that,” said Williams.
When carrying out inspections and taking follow-up actions, FDA will treat all firms equally, no matter what size the business, said Williams. When a manufacturer is inspected, the business’ management receives a list of observations from the FDA inspectors, who then submit the observations to their district office for a decision on what, if any, actions should be taken. Sometimes an inspector observes problems that can be corrected on the spot. Other times, problems are observed that will take longer to correct, and the inspector is given a verbal commitment that the firm will correct the errors. Depending on the type and seriousness of errors, FDA might do a follow-up inspection. Firms with more serious observations tend to be inspected more frequently, he added.
“Our inspectors do not go in with the intent of closing down a business,” said Williams, adding that inspections are generally a learning opportunity for both the company and for FDA.
The University of Mississippi (UM) has been participating in the training of FDA inspectors on dietary supplement GMPs and will continue to do so through next year, said Ikhlas Khan, PhD, director of UM’s FDA training program and a research professor at UM’s National Center for Natural Products Research (e-mail, September 15, 2009). The training focuses on the straightforward aspects of the GMP rule, such as sanitation, batch records, personnel training, and record keeping, as well as the more difficult activity of identity testing, he added.
“[Inspector training is] important since [dietary supplement] GMPs are different than drugs and foods and requires different skill sets,” said Dr. Khan.
Impact on Businesses
With GMP inspections now entering their second phase, the rule’s impact can be better observed.
“I’m sure all of us are nervous, no matter how big or how small, because when FDA comes in, it’s a big deal,” said Gagnon of Herbs, Etc., who is also the chairperson of AHPA’s small business committee.
Among small and very small businesses, Gagnon said he has noticed 2 main reactions to the GMP rule, with the most common response being thorough preparation. The remaining small and very small companies, which are usually not members of trade organizations, seem to be saying that if they get inspected, they will shut down their business, he continued.
Some of these companies might think that attempting GMP compliance will be too complicated, too expensive, too tedious, or that the necessary business-oriented preparation goes against the “healing” philosophy that initially brought them into the small herbal industry, said Gagnon.
“I think we’re going to see a lot of the smaller companies disappear at the end of the year,” he said, adding that this will be a huge loss to the industry because these small businesses contribute a great deal to industry education and innovation.
He added that many of the smaller businesses that primarily manufacture vitamin and mineral supplements, which often contain numerous ingredients, might have a harder time in achieving compliance than other companies. Identifying and/or certifying the ingredients of such products is much more difficult and expensive than identifying whole materials and simpler formulas, and it often requires finding the right testing technology and completing more tests, he added.
AHPA’s McGuffin echoed the significance of the complexity of a company’s products when considering impact.
“If the operation is pretty simple, you have less work to do than if it is very complicated,” he said. “There is much greater ease in identifying herbs in whole form than when you have powdered or extracted it.”
For this reason, he said, it seems that larger companies are not necessarily having an easier time than the smaller ones.
“It seems like it’s a lot of work for everybody,” said McGuffin.
According to McGuffin, companies that manufacture and sell original products are also likely to be more significantly impacted by GMP compliance. Because some of the manufacturing activities required for GMP compliance might appear to be expensive or confusing, some of these businesses will probably transition to using contract manufacturers, he said. Though he anticipates a move away from integrated companies to those focused either on marketing or on manufacturing, this will not be a universal shift, he added.
With most of the supplement industry hard at work to be GMP-compliant, it remains to be seen if the new regulations will have an impact on supplement quality and price.
“I think it’s inevitable that [the rule] will achieve what it set out to do as long as it is enforced,” said McGuffin.
The biggest impact on supplement quality will most likely be for manufacturers who thought they were producing quality products but were making unintentional errors, he said. As companies in the industry increase their manufacturing diligence, most of those mistakes will be prevented, or once realized, will be corrected.
“The quality of supplements from high quality companies are still [going to be] excellent, just as they were 5 years ago, 10 years ago,” McGuffin added.
“I think [the rule] will be a tremendous help,” said Gagnon. “I think it’s making a lot of companies have to step up. The consumer basically wins in that process.”
Because the processes needed to ensure the quality of products often impose higher costs on the manufacturers, they usually pass this on to consumers, he continued.
“I don’t think its going to be a tremendous cost [on consumers]. It will be hardest for small to medium size supplement manufacturers who do vitamins and minerals. For them [affordability] is going to be a real challenge,” said Gagnon.
- Food and Drug Administration. 21 CFR Part 111 Current good manufacturing practice in manufacturing, packaging, labeling, or holding operations for dietary supplements: final rule. Federal Register. June 25, 2007; 72(121):34751-34958.
- Heller L. GMP inspections should focus on Utah, California. Nutraingredients-USA.com. January 20, 2009. Available at: http://www.nutraingredients-usa.com/ Regulation/GMP-inspections-could-focus-on-Utah-California. Accessed September 3, 2009.
- Starling S. FDA sued over ‘unclear’ GMP rules. Nutraingredients-usa.com. August 12, 2009. Available at: http://www.nutraingredients-usa.com/Regulation/FDAsued-over-unclear-GMP-rules. Accessed September 3, 2009.
- AHPA petitions FDA to reconsider some parts of cGMP [press release]. Silver Spring, MD: American Herbal Products Association; July 27, 2007.
- Shao A. Re: Docket no. 2007N-0186, CFSAN 200736. Petition to request an exemption from 100 percent identity testing of dietary ingredients: current good manufacturing practice in manufacturing, packaging, labeling, or holding operations for dietary supplements. October 24, 2007. Available at: http://www.crnusa. org/pdfs/CRN_GMP_IFR_Comments102407.pdf. Accessed September 3, 2009.
- Association requests clarification on the Interim Final Rule (IFR) Exemption Petitions for reduced identity testing under the dietary supplement cGMPs [press release]. Washington, DC: Natural Products Association; October 25, 2007.